Enantioselective Total Synthesis of (+)-Garsubellin A.

Abstract

Garsubellin A is a meroterpene capable of enhancing the enzyme choline acetyltransferase whose decreased level is believed to play a central role in the symptoms of Alzheimer's disease. Due to the potentially useful biological activity together with the novel bridged and fused cyclic molecular architecture, garsubellin A has garnered substantial synthetic interest, but its absolute stereostructure has been undetermined. We report here the first enantioselective total synthesis of (+)‐garsubellin A. Our synthesis relies on stereoselective fashioning of a cyclohexanone framework and double conjugate addition of 1,2‐ethanedithiol that promotes aldol cyclization to build the bicyclic [3.3.1] skeleton. The twelve‐step, protecting group‐free synthetic route has enabled the syntheses of both the natural (−)‐garsubellin A and its unnatural (+)‐antipode for biological evaluations.